It has been estimated that 50% of all newly identified childhood hearing losses are genetic in origin. Recent advances in molecular genetics make possible the isolation and characterization of most genes which influence the hearing process. Such information will enhance diagnostic accuracy, improve genetic counseling and lead to more effective methods of therapy. More importantly, the knowledge gained from these studies will provide a foundation for major advances in understanding of the molecular genetics of the auditory system. Progression from localization to characterization of an individual gene requires a highly integrated research program. We have assembled the staff and laboratory facilities required to carry out all stages of the process. A series of projects are proposed which will allow us to make progress on several genetic disorders as well as develop the professional relationships and technical expertise to operate at maximum efficiency. This program project grant brings together four separate projects, each of which focuses on a different problem related to the molecular genetics of hearing. The first project will use the exciting new technology of gene targeting to create a genetically correct mouse model for Alport Syndrome (nephritis and deafness). As we isolate genes for other hearing disorders, we will be able to apply the same technology to develop similar animal models. The second and third projects are directed towards finding and cloning of the Usher Syndrome type II gene which we have localized to chromosome 1q. Project four will carry out a genome search for Branchio-Oto-Renal syndrome. Once the BOR gene is localized, we intend to apply the techniques outlined in the preceding projects to determine the molecular basis of that disorder. This program project will bring diverse investigators together to meet a common goal: the further understanding of the molecular genetic basis of normal and abnormal hearing. As such, it lays the foundation for future collaboration between the program investigators and gives the program a long term commitment to the study of the genetics of hearing disorders. This is particularly attractive when viewed in the context of the location of the project: BTNRH has existing auditory research programs that can take full advantage of the research proposed in this grant.